Human Immunodeficiency Virus (HIV) is a retrovirus that infects the immune system of humans. The viral genome becomes integrated within the cellular DNA, resulting in chronic permanent infection. Although virus may remain latent for a period of time, eventually the immune system becomes overwhelmed, causing severe opportunistic infections and neoplasms, in the absence of antiretroviral therapy. Current antiretroviral therapy consists of drugs targeted to steps in the viral life cycle that occur subsequent to infection of the cell, such as HIV integrase, HIV reverse transcriptase, HIV protease inhibitors. One of the main problems is the high mutability of HIV, so that drug-resistant strains rapidly develop, increasing the risk of treatment failure. This is mitigated by using a cocktail of drugs targeting different viral proteins.
Currently there is one FDA-approved entry inhibitor targeting the human CCR5 receptor, which HIV uses as a coreceptor for entry. The HIV envelope glycoprotein transmembrane subunit gp41 also plays an indispensable role in entry, by being responsible for viral fusion. The core of the gp41 hairpin consists of a parallel trimeric coiled-coil of N-terminal heptad repeats (NHR) with the C-terminal heptads repeat (CHR) wrapped down the outside in an anti-parallel fashion.
Fuzeon® (a registered trademark of Hoffmann-La Hoffman LaRoche Inc., of Nutley, N.J.), also called T20, was approved by the FDA as the first in a new class of anti-HIV drugs—HIV fusion inhibitors. It is believed to interact with the gp41 NHR and block the fusion between the viral and the target cell membranes (see Champagne, K.; Shishido, A.; Root, M. J. Interactions of HIV-1 inhibitory peptide T20 with the GP41 N-HR coiled coil. J Biol Chem 2008). However peptidic therapeutics suffer from low or non-existent oral bioavailability and high cost, which limit their clinical application. Given the severity and prevalence of HIV infection in humans, new therapies are needed.